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Clinical trial registration: a statement from the International Committee of Medical Journal Editors
Comment
Clinical trial registration: a statement from the International Committee of Medical Journal Editors Altruism and trust lie at the heart of research on human subjects. Altruistic individuals volunteer for research because they trust that their participation will contribute to improved health for others and that researchers will minimise risks to participants. In return for the altruism and trust that make clinical research possible, the research enterprise has an obligation to conduct research ethically and to report it honestly. Honest reporting begins with revealing the existence of all clinical studies, even those that reflect unfavourably on a research sponsor’s product. Unfortunately, selective reporting of trials does occur, and it distorts the body of evidence available for clinical decision-making. Researchers (and journal editors) are generally most enthusiastic about the publication of trials that show either a large effect of a new treatment (positive trials) or equivalence of two approaches to treatment (non-inferiority trials). Researchers (and journals) typically are less excited about trials that show that a new treatment is inferior to standard treatment (negative trials) and even less interested in trials that are neither clearly positive nor clearly negative, since inconclusive trials will not in themselves change practice. Irrespective of their scientific interest, trial results that place financial interests at risk are particularly likely to remain unpublished and hidden from public view. The interests of the sponsor or authors notwithstanding, anyone should be able to learn of any trial’s existence and its important characteristics. The case against selective reporting is particularly compelling for research that tests interventions that could enter mainstream clinical practice. Rather than a single trial, it is usually a body of evidence, consisting of many studies, that changes medical practice. When research sponsors or investigators conceal the presence of selected trials, these studies cannot influence the thinking of patients, clinicians, other researchers, and experts who write practice guidelines or decide on insurance-coverage policy. If all trials are registered in a public repository at their inception, every trial’s existence is part of the public record and the many stakeholders in clinical research can explore the full range of clinical evidence. We are far from this ideal at present, since trial registration is largely voluntary, registry data sets and public access to them varies, and registries contain only a small proportion of trials. In this editorial, published simultaneously in all member journals, the International Committee of Medical Journal Editors (ICMJE) proposes comprehensive trials registration as a solution to the problem of selective awareness and announces that all eleven ICMJE member journals will adopt a trials-registration policy to promote this goal. www.thelancet.com Vol 364 September 11, 2004
The ICMJE member journals will require, as a condition of consideration for publication, registration in a public trials registry. Trials must register at or before the onset of patient enrolment. This policy applies to any clinical trial starting enrolment after July 1, 2005. For trials that began enrolment before this date, the ICMJE member journals will require registration by Sept 13, 2005, before considering the trial for publication. We speak only for ourselves, but we encourage editors of other biomedical journals to adopt similar policies. For this purpose, the ICMJE defines a clinical trial as any research project that prospectively assigns human subjects to intervention or comparison groups to study the cause-andeffect relationship between a medical intervention and a health outcome. Studies designed for other purposes, such as to study pharmacokinetics or major toxicity (eg, phase I trials), would be exempt. The ICMJE does not advocate one particular registry, but its member journals will require authors to register their trial in a registry that meets several criteria. The registry must be accessible to the public at no charge. It must be open to all prospective registrants and managed by a not-for-profit organisation. There must be a mechanism to ensure the validity of the registration data, and the registry should be electronically searchable. An acceptable registry must include at minimum the following information: a unique identifying number, a statement of the intervention (or interventions) and comparison (or comparisons) studied, a statement of the study hypothesis, definitions of the primary and secondary outcome measures, eligibility criteria, key trial dates (registration date, anticipated or actual start date, anticipated or actual date of last follow-up, planned or actual date of closure to data entry, and date trial data considered complete), target number of subjects, funding source, and contact information for the principal investigator. To our knowledge, at present, only http://www.clinicaltrials.gov,
Published online September 9, 2004 http://image.thelancet.com/ extras/04cmt265web.pdf
911
Comment
sponsored by the United States National Library of Medicine, meets these requirements; there may be other registries, now or in the future, that meet all these requirements. Registration is only part of the means to an end; that end is full transparency with respect to performance and reporting of clinical trials. Research sponsors may argue that public registration of clinical trials will result in unnecessary bureaucratic delays and destroy their competitive edge by allowing competitors full access to their research plans. We argue that enhanced public confidence in the research enterprise will compensate for the costs of full disclosure. Patients who volunteer to participate in clinical trials deserve to know that their contribution to improving human health will be available to inform health-care decisions. The knowledge made possible by their collective altruism must be accessible to everyone. Required trial registration will advance this goal.
Catherine De Angelis, Editor-in-Chief, JAMA Jeffrey M Drazen, Editor-in-Chief, New England Journal of Medicine Frank A Frizelle, Editor, New Zealand Medical Journal Charlotte Haug, Editor-in-Chief, Norwegian Medical Journal John Hoey, Editor, CMAJ Richard Horton, Editor, The Lancet Sheldon Kotzin, Executive Editor, MEDLINE Christine Laine, Senior Deputy Editor, Annals of Internal Medicine Ana Marusic, Editor, Croatian Medical Journal A John P M Overbeke, Executive Editor, Nederlands Tijdschrift voor Geneeskunde (Dutch Journal of Medicine) Torben V Schroeder, Editor, Journal of the Danish Medical Association Hal C Sox, Editor, Annals of Internal Medicine Martin B Van Der Weyden, Editor, Medical Journal of Australia
How can cross-country research on health risks strengthen interventions? Lessons from INTERHEART Published online September 3, 2004 http://image.thelancet.com/ extras/04cmt296web.pdf See Articles pages 937 and 953
912
In today’s Lancet, the INTERHEART study investigators report a well-coordinated study of risk factors for myocardial infarction in multiple populations. They present hazard ratios and population-attributable fractions for multiple well-established physiological and behavioural risk factors. In a second analysis, the more challenging question of psychosocial risk factors is examined. Through coordination of primary-data collected in 52 countries worldwide, INTERHEART takes an important step towards identifying current intervention options and subsequent research needs for some of the most important globalhealth risks. Unlike analyses of mortality, which have traditionally been done by actuaries and demographers,1 much of the research on risk factors has emanated from disciplines such as epidemiology and toxicology. This knowledge has had tremendous influence on reducing important causes of disease, from smoking to hypertension. It is of course impractical to do a risk-factor study in every population in the world and on a regular basis (after all populations differ both over time and space). Therefore, addressing the broader issue of population effects of exposure to risks has required model-based extrapolations, either for individual risk factors2,3 or for groups of risks.4–6 Although it is widely acknowledged that such estimates are essential for informing policies and assessing interventions, the debate about cross-population extrapolation of hazard and its implications persist. The INTERHEART analyses provide important evidence on generalisability of risks. At the most basic level, the INTERHEART investigators show that factors such as hypertension, smoking, and
obesity increase the risk of myocardial infarction, as the existing epidemiology would predict. The scale of data collection, however, necessitated a more limited analysis than possible in single-risk or single-population studies, which have, for example, examined blood pressure or bodyweight along a continuum7,8 and have used measured versus self-reported blood pressure and diabetes. The contribution of INTERHEART is, therefore, less in establishing the magnitude of hazard for these risks than in providing evidence on similarity or variability of hazards across populations. One of the most informative results of INTERHEART is the demarcation of risks for which consistent hazards were noticeable across populations from those with greater apparent variability. Hazard consistency was most noticeable for risks with well-defined exposure indicators, including hypertension, blood lipids, obesity, and smoking (smoking is complicated by the need to account for accumulated exposure2). The observed consistency confirms previous findings from large cohorts, such as similarity of hazards per unit change in blood pressure and blood lipids between European and North American7,9 and Asia/Pacific studies,10,11 or consistency of hazards for smoking when stratified on serum cholesterol.12 Therefore, INTERHEART provides further confirmation that, for such factors, differences in total risk across populations are more a result of variations in exposure and background levels of disease than an outcome of different causal processes (table).3,6 For these risks, in parallel to advancing our basic understanding of causative mechanisms, we can safely begin to pay attention to design of effective interventions, www.thelancet.com Vol 364 September 11, 2004
Clinical trial registration: a statement from the International Committee of Medical Journal Editors Altruism and trust lie at the heart of research on human subjects. Altruistic individuals volunteer for research because they trust that their participation will contribute to improved health for others and that researchers will minimise risks to participants. In return for the altruism and trust that make clinical research possible, the research enterprise has an obligation to conduct research ethically and to report it honestly. Honest reporting begins with revealing the existence of all clinical studies, even those that reflect unfavourably on a research sponsor’s product. Unfortunately, selective reporting of trials does occur, and it distorts the body of evidence available for clinical decision-making. Researchers (and journal editors) are generally most enthusiastic about the publication of trials that show either a large effect of a new treatment (positive trials) or equivalence of two approaches to treatment (non-inferiority trials). Researchers (and journals) typically are less excited about trials that show that a new treatment is inferior to standard treatment (negative trials) and even less interested in trials that are neither clearly positive nor clearly negative, since inconclusive trials will not in themselves change practice. Irrespective of their scientific interest, trial results that place financial interests at risk are particularly likely to remain unpublished and hidden from public view. The interests of the sponsor or authors notwithstanding, anyone should be able to learn of any trial’s existence and its important characteristics. The case against selective reporting is particularly compelling for research that tests interventions that could enter mainstream clinical practice. Rather than a single trial, it is usually a body of evidence, consisting of many studies, that changes medical practice. When research sponsors or investigators conceal the presence of selected trials, these studies cannot influence the thinking of patients, clinicians, other researchers, and experts who write practice guidelines or decide on insurance-coverage policy. If all trials are registered in a public repository at their inception, every trial’s existence is part of the public record and the many stakeholders in clinical research can explore the full range of clinical evidence. We are far from this ideal at present, since trial registration is largely voluntary, registry data sets and public access to them varies, and registries contain only a small proportion of trials. In this editorial, published simultaneously in all member journals, the International Committee of Medical Journal Editors (ICMJE) proposes comprehensive trials registration as a solution to the problem of selective awareness and announces that all eleven ICMJE member journals will adopt a trials-registration policy to promote this goal. www.thelancet.com Vol 364 September 11, 2004
The ICMJE member journals will require, as a condition of consideration for publication, registration in a public trials registry. Trials must register at or before the onset of patient enrolment. This policy applies to any clinical trial starting enrolment after July 1, 2005. For trials that began enrolment before this date, the ICMJE member journals will require registration by Sept 13, 2005, before considering the trial for publication. We speak only for ourselves, but we encourage editors of other biomedical journals to adopt similar policies. For this purpose, the ICMJE defines a clinical trial as any research project that prospectively assigns human subjects to intervention or comparison groups to study the cause-andeffect relationship between a medical intervention and a health outcome. Studies designed for other purposes, such as to study pharmacokinetics or major toxicity (eg, phase I trials), would be exempt. The ICMJE does not advocate one particular registry, but its member journals will require authors to register their trial in a registry that meets several criteria. The registry must be accessible to the public at no charge. It must be open to all prospective registrants and managed by a not-for-profit organisation. There must be a mechanism to ensure the validity of the registration data, and the registry should be electronically searchable. An acceptable registry must include at minimum the following information: a unique identifying number, a statement of the intervention (or interventions) and comparison (or comparisons) studied, a statement of the study hypothesis, definitions of the primary and secondary outcome measures, eligibility criteria, key trial dates (registration date, anticipated or actual start date, anticipated or actual date of last follow-up, planned or actual date of closure to data entry, and date trial data considered complete), target number of subjects, funding source, and contact information for the principal investigator. To our knowledge, at present, only http://www.clinicaltrials.gov,
Published online September 9, 2004 http://image.thelancet.com/ extras/04cmt265web.pdf
911
Comment
sponsored by the United States National Library of Medicine, meets these requirements; there may be other registries, now or in the future, that meet all these requirements. Registration is only part of the means to an end; that end is full transparency with respect to performance and reporting of clinical trials. Research sponsors may argue that public registration of clinical trials will result in unnecessary bureaucratic delays and destroy their competitive edge by allowing competitors full access to their research plans. We argue that enhanced public confidence in the research enterprise will compensate for the costs of full disclosure. Patients who volunteer to participate in clinical trials deserve to know that their contribution to improving human health will be available to inform health-care decisions. The knowledge made possible by their collective altruism must be accessible to everyone. Required trial registration will advance this goal.
Catherine De Angelis, Editor-in-Chief, JAMA Jeffrey M Drazen, Editor-in-Chief, New England Journal of Medicine Frank A Frizelle, Editor, New Zealand Medical Journal Charlotte Haug, Editor-in-Chief, Norwegian Medical Journal John Hoey, Editor, CMAJ Richard Horton, Editor, The Lancet Sheldon Kotzin, Executive Editor, MEDLINE Christine Laine, Senior Deputy Editor, Annals of Internal Medicine Ana Marusic, Editor, Croatian Medical Journal A John P M Overbeke, Executive Editor, Nederlands Tijdschrift voor Geneeskunde (Dutch Journal of Medicine) Torben V Schroeder, Editor, Journal of the Danish Medical Association Hal C Sox, Editor, Annals of Internal Medicine Martin B Van Der Weyden, Editor, Medical Journal of Australia
How can cross-country research on health risks strengthen interventions? Lessons from INTERHEART Published online September 3, 2004 http://image.thelancet.com/ extras/04cmt296web.pdf See Articles pages 937 and 953
912
In today’s Lancet, the INTERHEART study investigators report a well-coordinated study of risk factors for myocardial infarction in multiple populations. They present hazard ratios and population-attributable fractions for multiple well-established physiological and behavioural risk factors. In a second analysis, the more challenging question of psychosocial risk factors is examined. Through coordination of primary-data collected in 52 countries worldwide, INTERHEART takes an important step towards identifying current intervention options and subsequent research needs for some of the most important globalhealth risks. Unlike analyses of mortality, which have traditionally been done by actuaries and demographers,1 much of the research on risk factors has emanated from disciplines such as epidemiology and toxicology. This knowledge has had tremendous influence on reducing important causes of disease, from smoking to hypertension. It is of course impractical to do a risk-factor study in every population in the world and on a regular basis (after all populations differ both over time and space). Therefore, addressing the broader issue of population effects of exposure to risks has required model-based extrapolations, either for individual risk factors2,3 or for groups of risks.4–6 Although it is widely acknowledged that such estimates are essential for informing policies and assessing interventions, the debate about cross-population extrapolation of hazard and its implications persist. The INTERHEART analyses provide important evidence on generalisability of risks. At the most basic level, the INTERHEART investigators show that factors such as hypertension, smoking, and
obesity increase the risk of myocardial infarction, as the existing epidemiology would predict. The scale of data collection, however, necessitated a more limited analysis than possible in single-risk or single-population studies, which have, for example, examined blood pressure or bodyweight along a continuum7,8 and have used measured versus self-reported blood pressure and diabetes. The contribution of INTERHEART is, therefore, less in establishing the magnitude of hazard for these risks than in providing evidence on similarity or variability of hazards across populations. One of the most informative results of INTERHEART is the demarcation of risks for which consistent hazards were noticeable across populations from those with greater apparent variability. Hazard consistency was most noticeable for risks with well-defined exposure indicators, including hypertension, blood lipids, obesity, and smoking (smoking is complicated by the need to account for accumulated exposure2). The observed consistency confirms previous findings from large cohorts, such as similarity of hazards per unit change in blood pressure and blood lipids between European and North American7,9 and Asia/Pacific studies,10,11 or consistency of hazards for smoking when stratified on serum cholesterol.12 Therefore, INTERHEART provides further confirmation that, for such factors, differences in total risk across populations are more a result of variations in exposure and background levels of disease than an outcome of different causal processes (table).3,6 For these risks, in parallel to advancing our basic understanding of causative mechanisms, we can safely begin to pay attention to design of effective interventions, www.thelancet.com Vol 364 September 11, 2004